CN111032636B - 6-chromanol derivative and synthesis thereof - Google Patents

6-chromanol derivative and synthesis thereof Download PDF

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CN111032636B
CN111032636B CN201880056735.2A CN201880056735A CN111032636B CN 111032636 B CN111032636 B CN 111032636B CN 201880056735 A CN201880056735 A CN 201880056735A CN 111032636 B CN111032636 B CN 111032636B
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拉斐尔·布玛
维尔纳·邦拉蒂
简-马克·德尔福
马塞尔·约瑞伊
乔纳森·艾伦·米德洛克
托马斯·涅斯切
杜梅尼科·索里亚诺
雷奈·托拜厄斯·史德姆勒
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Abstract

The present invention relates to novel compounds which are particularly useful for the synthesis of novel chromanol derivatives. These compounds have interesting properties. In particular, the novel chromanol derivatives have interesting antioxidant properties as well as flavor and aroma.

Description

6-chromanol derivative and synthesis thereof
Technical Field
The present invention relates to novel compounds which are particularly useful for the synthesis of novel chromanol derivatives.
Background
The field of isoprenoids and derivatives thereof is the chemical field in which many synthetic studies have been conducted. One of the reasons is that they are precursors of vitamin E, especially for alpha-tocopherol, which are very important compounds found in nature, and also important for the food and feed market. In this case, isoprenoids β -farnesene and β -myrcene are considered interesting starting compounds. As early as 30 years ago,
Figure BDA0002396721080000011
intensive research has been conducted in this area, such as U.S. patent 4,460,786, U.S. patent 4,621,165 and U.S. patent 5,874,636.CN 105859534A and WO 2015/165959 A1 disclose β -farnesene as a potential starting material for the synthesis of farnesyl acetone.
Myrcene is a naturally derived compound found in large amounts in a variety of plant essential oils, including laurel, hemp, ylang, wild thyme, parsley, cardamon, and hops. In addition, it is made from β -pinene obtained from turpentine. Beta-myrcene is therefore a readily available, sustainable and interesting starting material for the synthesis of more complex chemicals.
Summary of The Invention
Unexpectedly, we have found a series of heretofore unknown compounds with very interesting properties, which can be derived from myrcene. In a series of different reactions involving these novel compounds, new chromanol derivatives were eventually discovered. Such compounds have, among other properties, particularly interesting antioxidant behaviour. In view of the close structural relationship with tocopherols, this new compound has the highest interest in the research community as well as in the food and feed industry. It is particularly important to evaluate their potential impact on an organism.
Furthermore, intermediates in this synthesis have been found to possess interesting olfactory properties. In particular, they have a different odor and give a different olfactory impression than the corresponding compounds known.
This provides some new applications of great interest in the fields of flavour (flavour) and fragrance (perfume), in particular in the field of perfumes, which are achieved by the compounds available according to the invention. In general, odors, especially complex olfactory impressions, are difficult to predict, or even impossible to predict. Thus, any new odor, alone or in combination, that produces an olfactory impression is of great value to the fragrance, flavor and fragrance industry.
Other aspects of the invention are the subject matter of the other independent claims. Particularly preferred embodiments are the subject matter of the dependent claims.
Detailed Description
In one aspect, the present invention relates to compounds of formula (I)
Figure BDA0002396721080000021
Wherein R is 1 、R 3 And R is 4 Independently of one another, hydrogen or methyl;
R 2 represents hydrogen or R 2' ，R 2' Is a phenolic protecting group;
and wherein each x marks a chiral/stereogenic center, and # marks a chiral/stereogenic center.
For clarity, some terms used herein are defined below:
herein, "C x-y An alkyl group "is an alkyl group containing from x to y carbon atoms, i.e., for example, C 1-3 Alkyl is an alkyl group comprising 1 to 3 carbon atoms. The alkyl group may be linear or branched. For example-CH (CH) 3 )-CH 2 -CH 3 Is regarded as C 4 -an alkyl group.
“C x-y Alkylene "is alkylene containing from x to y carbon atoms, i.e. for example, C 1-3 Alkylene is an alkylene group comprising 1 to 3 carbon atoms. The alkylene group may be linear or branched. For example, -CH 2 -CH 2 -CH 2 -and-CH (CH) 3 )-CH 2 -and-C (CH) 2 -CH 3 ) -and C (CH) 3 ) 2 All considered to be C 3 -an alkylene group.
In this document, where a group or symbol is identically marked in a plurality of formulae, the definition of the group or symbol in the context of a particular formula applies to other formulae which contain the same marking.
The expression "method of preparing … …" is synonymous with "method of preparation" and may be used interchangeably.
The configuration of the asymmetrically substituted carbon center is indicated with the label R or S according to the rules defined by r.s.cahn, c.k.ingold and v.prelog. Such R/S concepts and rules for determining absolute configuration in stereochemistry are known to those skilled in the art.
Herein, any single dot-dashed line in the formulae represents a bond where a substituent is bound to the remainder of the molecule.
Any wavy line in any formula herein means a carbon-carbon bond that is linked to an adjacent carbon-carbon double bond such that the carbon-carbon double bond has a Z-or E-configuration. In other words, the formula with wavy lines represents the formula covering the E isomer as well as the Z isomer.
In any of the formulae herein, the x and # designate asymmetrically substituted carbon atoms, which are chiral/stereogenic centers.
In formula (I), R 2 Represents hydrogen or a phenolic protecting group. Thus, formula (I) includes both embodiments. Both embodiments have the formula (I-A) or (I-B), which are discussed below.
In one embodiment of the invention, R 2 Represents hydrogen. In this case, the compound of formula (I) is a compound of formula (I-A).
Figure BDA0002396721080000031
In another embodiment of the present invention, R 2 Is R 2' ，R 2' Represents a phenolic protecting group. Thus, this embodiment of formula (I) has formula (I-B)
Figure BDA0002396721080000041
Wherein R is 2' Represents a phenolic protecting group.
The phenol protecting group is a group protecting the phenol group (OH in formula (I-a)), and this protecting group can be easily removed, i.e. by prior art methods, to again give the corresponding compound with a free phenol group.
The phenolic protecting group is introduced by chemical reaction of a compound of formula (I-A) with a protecting agent.
Protective agents that result in the corresponding phenolic protecting groups are known to those skilled in the art, and the chemistry and conditions of the reaction are also known to those skilled in the art. For example, if the phenolic protecting group forms an ester with the rest of the molecule, suitable protecting agents are, for example, acids, anhydrides or acid halides.
Phenol protecting group R 2' In particular selected from the group consisting of:
Figure BDA0002396721080000042
wherein R is 10 And R is 11 Independently of each other, represent C 1-15 -alkyl or fluorinated C 1-15 -alkyl or C 1-15 -cycloalkyl or C 7-15 -an aralkyl group;
R 12 represent C 1-15 Alkylene or C 6-15 -an alkylene group;
and wherein either
R 13 Represent C 1-15 -alkyl or alkylene oxyalkyl or polyoxyalkylene;
R 14 represents hydrogen or C 1-15 -an alkyl group;
either or
R 13 And R is 14 Together represent C forming a 5-to 7-membered ring 3-7 -an alkylene group;
and wherein Y is 1 、Y 2 And Y 3 Independently of one another, hydrogen or a group of the formula
Figure BDA0002396721080000051
And wherein the single dot-dashed line represents a bond through which the substituent is bound to the remainder of the molecule.
If R is 2' Equal to R 10 The compounds of formula (I) are ethers which can be formed by reaction of the corresponding protecting agents with the phenol (OH) groups of the compounds of formula (I-A). In this case, the protecting agent may be, for example, an alkylating agent, for example, the respective C 1-15 -alkyl or fluorinated C 1-15 -alkyl or C 1-15 -cycloalkyl or C 7-15 Aralkyl halides, in particular iodides.
In a preferred embodiment, R 10 Is methyl.
In another preferred embodiment, R 10 Is C 7-15 Aralkyl, preferably benzyl or substituted benzyl, particularly preferably benzyl. If R is 2' From the following components
Figure BDA0002396721080000052
Represented by the formula (I)Is an ester of a carboxylic acid or dicarboxylic acid, which can be formed by reacting the respective protecting agent with the phenolic (OH) group of the compound of formula (I-A). In this case, the protective agent may be, for example, an anhydride or a halide of the corresponding carboxylic acid (1) or dicarboxylic acid (2).
(1)
Figure BDA0002396721080000053
(2)
Figure BDA0002396721080000054
If the compound of formula (I) is an ester of a carboxylic acid or dicarboxylic acid, R is preferably 2' Is C 1-7 -an acyl group, preferably acetyl, trifluoroacetyl, propionyl or benzoyl, or a substituted benzoyl group.
Esters are easily deprotected by the action of an acid or base.
If R 2' Is that
Figure BDA0002396721080000061
The compound of formula (I) is an acetal which can be formed by reaction of the corresponding protecting agent with the phenol (OH) group of the compound of formula (I-a). In this case, the protective agent may be, for example, the corresponding aldehyde, alkyl halide, e.g., meO (CH) 2 ) 2 OCH 2 Cl or enols, for example 3, 4-dihydro-2H-pyran.
In this case, the substituent R 2' Preferably is
Figure BDA0002396721080000062
Where n=0 or 1.
In some cases, acetals are also referred to as "ethers", especially in the above cases: methoxymethyl ether (MOM-ether), beta-methoxyethoxy-methyl ether (MEM-ether) or tetrahydropyranyl ether (THP-ether).
Under the influence of acids, acetals are easily deprotected.
In another preferred embodiment, the compound of formula (I) is an ester of phosphoric acid, pyrophosphoric acid, phosphorous acid, sulfuric acid or sulfurous acid.
Depending on the different reaction conditions, the esterification is complete or partial, so that some of the residual acid groups of the corresponding acids are not esterified (i.e., Y 1 And/or Y 2 And/or Y 3 ＝H)。
Most preferably, the protecting group R 2' Is benzoyl or C 1-4 Acyl, in particular acetyl or trifluoroacetyl, more in particular acetyl. Wherein R is 2' Molecules representing acyl groups, in particular acetyl groups, can be readily prepared from the corresponding unprotected molecules by esterification reactions, and unprotected phenolic compounds can be obtained from the corresponding esters by ester hydrolysis.
R 1 、R 3 And R is 4 Independently of one another, hydrogen or methyl.
In all formulae of the invention, R is preferably 1 、R 3 And R is 4 Is a combination of the following:
R 1 ＝R 3 ＝R 4 ＝CH 3
or alternatively
R 1 ＝R 4 ＝CH 3 ，R 3 ＝H
Or alternatively
R 1 ＝H，R 3 ＝R 4 ＝CH 3
Or alternatively
R 1 ＝R 3 ＝H，R 4 ＝CH 3 。
Most preferred is substitution pattern R 1 ＝R 3 ＝R 4 ＝CH 3 。
As described above, R can be obtained from compounds of formula (I-A) 2 Represents R 2’ A compound of formula (I) (as protecting group). Accordingly, in another aspect, the present invention relates to a process for the preparation of a compound of formula (I-B), comprising the steps of:
a1 Providing a compound of formula (I-A)
Figure BDA0002396721080000071
a2 Reacting a compound of formula (I-A) with a protecting agent to give a compound of formula (I-B)
Figure BDA0002396721080000072
The compounds of formula (I-A) may be prepared in various ways. In a particularly suitable manner, it is synthesized from a compound of formula (II-A) or (II-B) and a compound of formula (III).
Accordingly, in a further aspect, the present invention relates to a process for preparing a compound of formula (I-a), comprising the steps of:
b1 Providing a compound of formula (II-A) or (II-B);
Figure BDA0002396721080000073
Figure BDA0002396721080000081
b2 Condensing a compound of formula (II-A) or (II-B) with a compound of formula (III) to give a compound of formula (I-A)
Figure BDA0002396721080000082
It has been found that the condensation reaction of step b 2) can be carried out in a manner analogous to the condensation of methylhydroquinone, dimethylhydroquinone and trimethylhydroquinone with the corresponding alcohols isophytol or phytol, respectively, as described, for example, in Ullmann's Encyclopedia of Industrial Chemistry (Ullmann encyclopedia of Industrial chemistry), 2010 release, 7 th edition, "Vitamins", pages 44-46.
For the condensation reaction (step b 2)), a series of catalysts, for example ZnCl, can be used 2 Mineral acid, BF 3 /AlCl 3 Fe/HCl, trifluoroAcetic acid or boric acid/carboxylic acid and indium (III) or scandium (III) salts, as disclosed in WO 2005/121115 A1. Furthermore, suitable catalysts are heteropolyacids, in particular 12-tungstophosphoric acid or 12-tungstophosphoric acid, as are disclosed, for example, in EP 0 970 953 A1.
In the condensation step b 2), the novel compounds of the formula (I-C) are obtained as intermediates.
Figure BDA0002396721080000083
Thus, the compounds of formula (I-C) represent another aspect of the invention.
Another method of preparing the compounds of formula (I-B) represents another aspect of the invention. The method comprises the following steps:
b1 Providing a compound of formula (II-A) or (II-B);
Figure BDA0002396721080000091
b3 Reacting a compound of formula (II-A) or (II-B) with a compound of formula (III-A) to give a compound of formula (I-B)
Figure BDA0002396721080000092
In the condensation step b 3), the compound of the formula (I-D) is obtained as an intermediate
Figure BDA0002396721080000093
Thus, the compounds of formula (I-D) represent another aspect of the invention.
The above reaction is not stereospecific and thus forms a mixture of isomers of formula (I-A) or (I-B) of R-and S-configuration at the chiral/stereogenic center marked with # at C-2. Typically, a diastereomeric mixture of about 50% of the 2S-and 50% of the 2R-isomer is formed at C-2 of formula (I-A).
The different stereoisomers may in principle be separated and isolated by chromatography-based techniques, in particular using chiral stationary phases, in particular as described in WO 2016/188945 A1 or WO 2012/152779 A1, the entire contents of which are incorporated herein by reference.
Thus, specific stereoisomers of formula (I) or (I-a) may be obtained wherein chiral/stereogenic centers marked with × and/or #, in particular chiral/stereogenic centers marked with #, have the desired configuration.
Thus, the process facilitates/allows to obtain compounds of formula (I) or (I-a) in a specific configuration, in particular in the (2 r,3'r,7' r) configuration, as shown in the following formula:
Figure BDA0002396721080000101
The compounds of formulae (II-A) and (II-B) mentioned above are novel and represent two further aspects of the invention.
Figure BDA0002396721080000102
In addition to their use as intermediates for the synthesis of the compounds of the formulae (I) and (I-A), respectively, they can also be used in the flavour and fragrance sector, in particular in the perfume sector, due to their odor.
We have found that the compounds of the above formula (II-B) can be obtained from the compounds of the formula (II-A) by isomerisation. Thus, in a further aspect, the present invention relates to a process for preparing a compound of formula (II-B) by isomerisation of a compound of formula (II-A)
Figure BDA0002396721080000111
Wherein the wavy line indicates a carbon-carbon bond which is in the Z-configuration or E-configuration when connected to a carbon-carbon double bond.
The method of isomerisation may be a method known to the person skilled in the art for isomerising isophytol to phytol by acid-catalyzed rearrangement, as described for example in the Ullmann's Encyclopedia of Industrial Chemistry,2010 release, 7 th edition, "Vitamins", pages 44-46.
We have found that the compounds of formula (II-A) described above can be obtained from compounds of formula (IV). Accordingly, in another aspect, the present invention relates to a process for preparing a compound of formula (II-A),
Figure BDA0002396721080000112
The method comprises the following steps:
b) Providing a compound of formula (IV);
Figure BDA0002396721080000113
the next step is
Either or
c1 Ethynylation of a compound of formula (IV) with acetylene in the presence of a basic substance to give a compound of formula (V)
Figure BDA0002396721080000121
c2 Hydrogenation of the compound of formula (V) with molecular hydrogen in the presence of a Lindlar catalyst to give the compound of formula (II-A);
either or
c3 Vinyl-forming a compound of formula (IV) by adding a vinyl grignard reagent to obtain a compound of formula (II-a);
details of the reaction types and conditions that can be used for the variants using step c 1) are disclosed in EP 1 532 092 B1, especially example 2, or in WO 2003/029175 A1 (using basic anion exchange resins), the entire contents of which are incorporated herein by reference. Hydrogenation with molecular hydrogen in the presence of Lindlar catalyst can be used in step c 2). For example, the methods and conditions disclosed by A.Ofner et al in Helv.Chim. Acta 1959,42,2577-2584, the entire contents of which are incorporated herein by reference, may be used for the combination of steps c 1) and c 2).
For example, US 4,028,385 discloses details of the reaction type and conditions using the variant of step c 3) and details regarding steps c 1) and c 2), which are incorporated herein by reference.
The compounds of formula (V) above are novel and represent another aspect of the invention.
Figure BDA0002396721080000122
As discussed above, the compound of formula (V) may be prepared by reaction c 1), i.e. by ethynylation of the compound of formula (IV) with acetylene in the presence of a basic substance.
The compounds of formula (IV) above are also novel and represent another aspect of the invention.
Figure BDA0002396721080000123
We have found that the compound of formula (IV) may be obtained from a compound of formula (VI). Accordingly, in another aspect, the present invention relates to a process for preparing a compound of formula (IV),
Figure BDA0002396721080000131
the method comprises the following steps:
d) Hydrogenating the compound of formula (VI) to obtain the compound of formula (IV)
Figure BDA0002396721080000132
Wherein the dashed line represents a carbon-carbon double bond at one of the two indicated positions.
In other words, the formula of the compound (VI) shown above is a schematic representation of the following two formulas (VI-a) and (VI-b)
Figure BDA0002396721080000133
In fact, since not only the pure molecules of formula (VI-a) or (VI-b) but also mixtures of formulae (VI-a) and (VI-b) can be used, they can be used as starting materials for the hydrogenation in step d). They all give the same product, namely the compound of formula (IV).
Preferably, for this reaction, a mixture of the formulae (VI-a) and (VI-b) is used as compound of the formula (VI) in step d) above.
The compounds of formula (VI) mentioned above are also novel and represent another aspect of the invention.
The hydrogenation of the compounds of the formula (VI) (VI-a) and/or (VI-b), respectively) to compounds of the formula (IV) can be carried out in step d) according to methods known to the person skilled in the art. Typically, hydrogenation involves reaction with molecular hydrogen in the presence of a noble metal catalyst. Preferably, the hydrogenation is carried out by molecular hydrogen in the presence of palladium on a mineral support. Particularly preferably, the noble metal catalyst is selected from palladium on carbon, silica (SiO 2 ) Palladium-supported TiO 2 Palladium and alumina (Al) 2 O 3 ) Palladium-loaded group.
The hydrogenation in step d) is preferably carried out under pressure, in particular between 1 and 20bar, more preferably between 1 and 6 bar.
It has been shown that compounds of the formula (VI) (VI-a) or (VI-b), respectively) can be obtained from compounds of the formula (VII) by reaction e).
Figure BDA0002396721080000141
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The dashed line in formula (VII) represents a carbon-carbon double bond located at one of the two indicated positions.
In other words, the formula of the compound (VII) shown above is schematically represented by the following two formulas (VII-a) and (VII-b)
Figure BDA0002396721080000142
In particular, the reaction e) is a Wittig (Wittig) reaction comprising the reaction of a compound of formula (VII) (VIII-a) or (VII-b), respectively, with 1- (triphenylphosphine) -2-propanone.
The compounds of formula (VII) shown above are also novel and represent another aspect of the invention.
It has been shown that the compounds of the formula (VII) (VII-a) or (VII-b), respectively) can be obtained from the compounds of the formula (VIII) (VIII-a) or (III-b), respectively) by reaction f).
Figure BDA0002396721080000143
The dashed line in formula (VIII) represents a carbon-carbon double bond located at one of the two indicated positions.
In other words, the formula of the compound (VIII) shown above is schematically represented by the following two formulas (VIII-a) and (VIII-b)
Figure BDA0002396721080000144
Reaction f) consists of: the ketone of formula (VIII) is reacted with Wittig of a (alkoxymethyl) triarylphosphonium salt in the presence of a base, and the enol ether formed is then hydrolyzed to the corresponding aldehyde under acidic conditions.
It has been shown that the compounds of the formula (VIII) (VIII-a) or (VIII-b), respectively) can be obtained from the compounds of the formula (IX) (IX-a) or (IX-b), respectively), by reaction g.
Figure BDA0002396721080000151
The dashed line in formula (IX) represents a carbon-carbon double bond at one of the two indicated positions.
In other words, the formula of the compound (IX) shown above is schematically represented by the following two formulas (IX-a) and (IX-b)
Figure BDA0002396721080000152
Reaction g) involves decarboxylation in the presence of water. Details of this reaction of similar compounds can be found in US 5,874,636.
It has been shown that the compounds of formula (IX), respectively (IX-a) or (IX-b), can be obtained from myrcene (formula (X)) and compounds of formula (XI) in the presence of a noble metal catalyst, in particular in the presence of a rhodium (I) catalyst, most preferably in the presence of a rhodium (I) complex with a suitable diene or acetylene as ligand, in particular in the presence of a water-soluble phosphine
Figure BDA0002396721080000153
In particular, suitable dienes are 1, 5-cyclooctadiene or norbornadiene. A preferred ligand is 1, 5-cyclooctadiene.
The reaction is advantageously based on
Figure BDA0002396721080000154
The processes described in patents US 4,460,786 and US 4,621,165 are incorporated herein by reference in their entirety.
In the formulae (IX), (IX-a), (IX-b) and (XI), the residue R 5 Represent C 1-10 Alkyl, in particular C 1-5 -alkyl, more particularly methyl.
In fig. 1 and 2, schemes of the synthetic pathways of the disclosed compounds of formula (I) are shown. The synthetic route starts from the commercially available starting materials myrcene (formula (X)) and alkyl 3-oxovalerate (XI) and uses different intermediates, in particular of the formulae (VII), (VI), (IV), (V), (II-A), (II-B) and (I-A). Details of these materials and their preparation in specific reaction steps are disclosed in the above description.
It has been observed that the above-mentioned substances, in particular compounds of the formula (IV), (V), (VI), (VII), (VIII), (IX), (II-A) or (II-B), in particular compounds of the formula (IV), (VI), (VII), (V), (II-A) or (II-B), or in particular compounds of the formula (IV), (VI), (VII), (VIII) or (IX), have various interesting properties and can be used for a variety of purposes. In particular, they are of great interest for use in the fields of flavour and fragrance, in particular in the field of perfumes, and as starting materials for molecules in the fields of pharmaceuticals, food and feed additives. They have very interesting odors, especially woody, fruit and even floral characteristics, which make the use of these substances very attractive in the fields of flavour and fragrance and perfume. Of particular interest are those materials that are used with other olfactory active materials to create a new olfactory impression.
The above mentioned compounds can be used in a wide variety of fragrance applications, for example in any field of advanced and functional perfumery, such as perfumes, household products, laundry products, body care products and cosmetics. The amount of the compound used may vary widely depending on the particular application and the nature and amount of the other odorant component.
These compounds may be used in fragrance applications by directly mixing the fragrance composition directly with the fragrance application, or they may be entrapped in an earlier step with an entrapment material (e.g. polymers, capsules, microcapsules and nanocapsules, liposomes, film formers, absorbents such as carbon or zeolites, cyclic oligosaccharides and mixtures thereof), or they may be chemically bonded to a substrate adapted to release the new compounds upon application of an external stimulus (e.g. light, enzymes, etc.) and then mixed with the application. As used herein, "fragrance application" refers to any product, for example, advanced fragrances, such as perfumes and eau de scents (eau de tolettes); household products, such as dishwashing detergents, surface cleaners; laundry products such as softeners, bleaches, detergents; body care products such as shampoos, body washes; and cosmetics, such as deodorants, vanishing creams, which contain a flavour enhancer. The list of products is given by way of illustration and is not to be construed as limiting in any way.
Furthermore, it has surprisingly been found that the compounds of formula (I) have particularly interesting antioxidant behaviour. In view of the close structural relationship with tocopherols, the novel compounds have the highest interest in the research community as well as in the food and feed industry. It is particularly important to evaluate their potential impact on an organism.
Of particular interest are any combination of the compounds of formula (I) with other antioxidants. Suitable further antioxidants are in particular antioxidants selected from the group consisting of Butylated Hydroxytoluene (BHT), butylated Hydroxyanisole (BHA), tert-butylhydroquinone (TBHQ), propyl gallate, vitamin a, vitamin C and vitamin E.
Of particular interest are compositions comprising a compound of formula (I) and a compound of formula (XI)
Figure BDA0002396721080000171
Examples
The invention is further illustrated by the following experiments.
Example 1:
examples of compounds of formula (IX): synthesis of methyl 2-geranyl-3-oxopentanoate
Reaction step h
A200 mL four-necked sulfonation flask equipped with a magnetic stirring bar, condenser, thermometer and argon adapter was inertized with argon and then charged with Na 2 CO 3 (42 mg,0.40mmol,99.8%,0.4 mol%), chloro (1, 5-cyclooctadiene) rhodium (I) dimer (60 mg,0.12mmol,0.24mol% [ Rh)]) 3,3',3"-phosphaneSodium tris (sodium 3,3',3 "-phosphanetrimbenzenesulfonate, 3.56g,5.95mmol,95%,6 mol%) and was dissolved in water (26 mL) and MeOH (6 mL). Methyl 3-oxopentanoate (15 mL,15.7g, 119mmol,1.2 eq.) and myrcene (19.0 mL,15g,99mmol,90%,1.0 eq.) were added and the two-phase mixture was heated to 100deg.C (oil bath) for 23 hours. The mixture was cooled to 23 ℃ and the phases separated. The organic phase was diluted with hexane (50 mL) and then washed with brine (2X 50 mL), with MgSO 4 Dried, filtered and concentrated in vacuo to give 24.0g of a colourless crude product. Subsequently, the product was purified by vacuum distillation at 145 ℃ (oil bath)/0.35 mbar, providing a two isomer mixture of methyl 2-geranyl-3-oxopentanoate ((E) -5, 9-dimethyl-2-propionyl-4, 8-dienoate and methyl 9-methyl-5-methylene-2-propionyl-8-enoate) as a colorless liquid (18.63 g, qnmr gave 95.7% purity, 68% yield). Both isomers have been characterized by MS and NMR.
Characterization of methyl 2-geranyl-3-oxopentanoate
GC-MS method. GC: column HP-5MS,30m x 0.25mm,0.25 μm; temperature ramp: the temperature is raised to 315 ℃ at +10 ℃/min and maintained for 15min. The total run time was 39.5min. MS: quadrupole mass spectrometer, EI.
GC-MS:51.5 area% (9-methyl-5-methylene-2-propionyl-dec-8-enoate), 41.7 area% ((E) -5, 9-dimethyl-2-propionyl-dec-4, 8-dienoic acid methyl ester).
m/z (9-methyl-5-methylene-2-propionyl-dec-8-enoic acid methyl ester,%) 266 (2, M + ),248[5,(M-H 2 O) + ],205(6),136(22),121(21),109(26),93(78),69(100),57(43),41(45),29(20)。
m/z ((E) -5, 9-dimethyl-2-propionyl-dec-4, 8-dienoic acid methyl ester,%) 266.1 (2, M) + ),248[1,(M-H 2 O) + ],197(10),137(29),136(29),121(19),109(58),93(19),81(20),69(71),57(100),41(44),29(22)。
1 H NMR (mixture of isomers, 300MHz, CHROFORM-d) δ1.05 (t, J=7.3 Hz, 1.4H), 1.06 (t, J=7.3 Hz, 1.6H), 1.56-1.63 (m, 4.5H), 1.64-1.70 (m, 3H), 1.92-2.15 (m) ,6.5H),2.40-2.68(m,3H),3.43-3.52(m,1H),3.70(s,1.3H),3.72(s,1.7H),4.72(br s,0.56H),4.77(d,J＝1.3Hz,0.57H),4.97-5.14(m,1.5H)ppm。
13 C NMR (mixture of isomers, 75MHz, CHROFORM-d) delta 7.53,7.59,16.0,17.63,17.64,25.6,26.19,26.28,26.5,27.1,33.7,35.4,35.6,39.6,52.22,52.27,57.8,58.5,110.2,119.7,123.86,123.93,131.5,131.7,138.4,147.9,170.08,170.28,205.64,205.66ppm.
Example 2: a compound of formula (VIII): 11-methyl-7-methylenedodec-10-en-3-one and (E) -7,11- Synthesis of dimethyldodeca-6, 10-dien-3-one
The reaction steps are as follows: g)
A100 mL four-necked flask equipped with a magnetic stirrer, condenser, dean-Stark trap, thermometer, argon adapter, syringe pump and oil bath was charged with methyl 2-geranyl-3-oxopentanoate (example 1) (mixture of two olefin isomers, 17.6g,63.3mmol, 95.7% by qNMR). The flask was heated to 190 ℃ (oil bath) and then water (2.0 ml,1.75 eq) was slowly added below the surface by syringe pump over 8 hours. The reaction was continued at 190 ℃ (oil bath) for an additional 13 hours, then the crude product was cooled to room temperature and diluted with hexane (50 mL). The solution was washed with water (3X 50 mL) and the combined aqueous phases were back-extracted with hexane (30 mL). The combined organic phases were dried over MgSO 4 Dried, filtered and concentrated in vacuo (40 ℃,120 to 1 mbar) to give a colorless residue (12.9 g). The crude product was purified by distillation to give a mixture of 11-methyl-7-methylenedodec-10-en-3-one and (E) -7, 11-dimethyldodec-6, 10-dien-3-one (10.2 g,48.7mmol, 99.3% by qNMR, ratio 54:46, 77% yield).
Characterization of the Compounds of formula (VIII)
GC-MS:53.6 area% (11-methyl-7-methylenedodec-10 en-3-one), 44.2 area% ((E) -7, 11-dimethyldodec-6, 10-dien-3-one);
m/z (11-methyl-7-methylenedodec-10-en-3-one,％)208(2,M + ),190[3,(M-H 2 O) + ],175(2),165(9),147(9),136(16),121(15),109(30),93(42),85(15),79(9),69(100),57(38),41(49),29(16)。
m/z ((E) -7, 11-dimethyldodeca-6, 10-dien-3-one,%) 208 (2, M + ),190[1,(M-H 2 O) + ],175(0.5),165(15),147(2),136(14),121(11),109(7),93(10),81(5),69(40),57(100),41(27),29(14)。
1 H NMR (mixture of double bond isomers, 300MHz, CHROFORM-d) δ1.06 (t, J=7.3 Hz, 3H), 1.60 (br s, 1.5H), 1.61 (br s, 3H), 1.69 (br s, 3H), 1.70-1.79 (m, 1H), 1.93-2.16 (m, 5H), 2.21-2.33 (m, 1H), 2.36-2.47 (m, 4H), 4.72 (br s, 0.55H), 4.75 (br s, 0.55H), 5.04-5.14 (m, 1.5H) ppm.
13 C NMR (mixture of double bond isomers, 75MHz, CHROFORM-d) delta 7.80,7.84,15.9,17.65,17.68,21.7,22.6,25.7,26.4,26.6,35.5,35.8,35.92,35.97,39.6,41.7,42.4,109.5,122.7,124.0,124.2,131.4,131.6,136.2,148.8,211.5,211.6ppm.
Example 3: a compound of formula (VII): (±) -2-ethyl-10-methyl-6-methyleneundec-9-enal and (E) Synthesis of 2-ethyl-6, 10-dimethylundec-5, 9-dienal
The reaction steps are as follows: f)
A350 mL four-necked flask equipped with a magnetic stirrer, condenser, addition funnel, thermometer, argon adapter, syringe pump and oil bath was inertized with argon, then charged with a mixture of (methoxymethyl) triphenylphosphonium chloride (45.2 mmol,99.7% (2.0 eq.) and suspended in anhydrous THF (100 mL.) the suspension was then cooled to-15℃and a solution of n-butyllithium (29.4 mL of 1.54M solution in hexane, 45.2mmol,2.0 eq.) in THF (20 mL) was slowly added over 35 minutes during which the solution became orange, the mixture was warmed to 0℃and stirred for 1 hour, 11-methyl-7-methylene-dodec-10-en-3-one and a mixture of (E) -7, 11-dimethyldodec-6, 10-dien-3-one (5.0 g,22.6mmol, purity 94.2% obtained by qNMR) were added dropwise over 45 minutes while maintaining the temperature at 0-5 ℃. The reaction was stirred at 0 ℃ for an additional 30 minutes. The reaction was allowed to warm to room temperature and stirred for 18 hours. Subsequently, the reaction was cooled to 0 ℃ and quenched with brine (100 mL) to give two liquid phases and a colorless precipitate. Adding water (50 mL) to dissolve the precipitate; the aqueous phase was extracted with ethyl acetate (3X 100 mL). The combined organic phases were washed with brine (2X 50 mL), and with MgSO 4 Dried, filtered and concentrated in vacuo to give a dark red oil from which a solid precipitated overnight at 4 ℃. The mixture was dissolved in heptane/ethyl acetate 95:5 and then filtered through a plug of silica gel. The plug was rinsed with additional heptane/ethyl acetate 95:5 and the combined filtrates concentrated in vacuo to give the crude enol ether (7.85 g,18.5mmol, 55.7% purity by qNMR, 82% yield).
To a 100mL four-necked flask equipped with a thermometer, magnetic stirrer, argon adapter, condenser and oil bath was added the above crude enol ether (2.25 g,5.30mmol,55.7%,1.0 eq.) and dissolved in acetone (48 mL) and water (12 mL). P-toluenesulfonic acid monohydrate (102 mg,0.53mmol,10mol%, 98.5%) was added and the resulting yellow solution was heated to 62 ℃ (reflux) for 10 hours. The reaction was cooled to room temperature and diluted with ethyl acetate (30 mL). The aqueous phase was extracted with ethyl acetate (2X 30 mL). The combined organic phases were washed with brine (2X 20 mL), with MgSO 4 Drying, filtration and concentration in vacuo gave the crude product as a yellow liquid (2.20 g,3.66mmol, 37.0% purity by qNMR, 69% yield) and purification by chromatography.
Characterization of the Compounds of formula (VII)
92.3 area% GC-MS;
m/z(％)222(2,M + ),204[3,(M-H 2 O) + ],179(8),161(16),150(3),135(9),109(27),95(13),81(14),69(100),55(11),41(45),29(7)。
1 H NMR(300MHz,CHLOROFORM-d)δ0.92(t,J＝7.4Hz,3H),1.40-1.75(m,12H),1.97-2.24(m,7H),4.72(br s,1H),4.74(br s,1H),5.06-5.16(m,1H),9.59(d,J＝3.1Hz,1H)ppm。
13 C NMR(75MHz,CHLOROFORM-d)δ11.5,17.7,21.9,25.1,25.7,26.4,28.1,35.9,36.1,53.3,109.2,124.1,131.6,149.0,205.5ppm。
example 4: a compound of formula (VI): (±) - (E) -5-ethyl-13-methyl-9-methylene-tetradecyl-3, 12-diyl Synthesis of alkene-2-ones
The reaction steps are as follows: e)
A100 mL four-necked flask equipped with a magnetic stirrer, condenser, thermometer, argon adapter and oil bath was inertized with argon, then charged with a mixture of 2-ethyl-10-methyl-6-methyleneundec-9-enal and (E) -2-ethyl-6, 10-dimethylundec-5, 9-dienal (example 3) (6.50 g,24.7mmol, purity 84.6% by qNMR, ratio-95:5, 1.0 eq.) and 1- (triphenylphosphine) 2-propanone (11.9 g,37.1mmol,99%,1.5 eq.) and dissolved in toluene (60 mL). The colorless suspension was heated to 125 ℃ (oil bath) for 26 hours. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was suspended in heptane (50 mL) and stirred at 23 ℃ for 30 min. The suspension was filtered and the filtrate concentrated in vacuo to give a yellow liquid (7.85 g). The crude product was purified by flash chromatography on silica gel (220 g), eluting with heptane/t-butyl methyl ether 100:0 to 90:10 (v/v), flow rate 150mL/min. Some of the combined fractions were purified again by flash chromatography and the combined product fractions provided (±) - (E) -5-ethyl-13-methyl-9-methylenetetradec-3, 12-dien-2-one (4.88 g,17.5mmol, 94.3% purity by qNMR, 71% yield).
Characterization of the Compounds of formula (VI)
GC-MS:96.3 area% ((E) -5-ethyl-13-methyl-9-methylenetetradeca-3, 12-dien-2-one)
m/z(％)262(3,M + ),244[1,(M-H 2 O) + ],233[1,(M-C 2 H 5 ) + ],219(3),201(3),189(3),178(5),161(13),149(7),135(21),122(17),109(49),95(36),81(23),69(100),55(19),41(59),29(4)。
1 H NMR(300MHz,CHLOROFORM-d)δ0.86(m,J＝7.3Hz,3H),1.25-1.59(m,6H),1.61(s,3H),1.69(d,J＝0.9Hz,3H),1.93-2.16(m,7H),2.25(s,3H),4.70(br s,1H),4.72(br s,1H),5.05-5.16(m,1H),6.04(dd,J＝15.9,0.7Hz,1H),6.56(dd,J＝15.9,9.1Hz,1H)ppm。
13 C NMR(75MHz,CHLOROFORM-d)δ11.64(s,1C),17.7(1C),25.3(1C),25.7(1C),26.4(1C),26.9(1C),27.2(1C),33.7(1C),35.9(1C),36.1(1C),44.5(1C),109.0(1C),124.1(1C),131.2(1C),131.5(1C),149.2(1C),152.4(1C),198.6(1C)ppm。
Example 5: a compound of formula (IV): synthesis of (all-rac) -5-ethyl-9, 13-dimethyltetradecan-2-one
The reaction steps are as follows: d)
(E) -5-ethyl-13-methyl-9-methylenetetradec-3, 12-dien-2-one (example 4) (3.18 g,11.3mmol, 93.5%) was dissolved in heptane (10 g) and treated with charcoal (1.00 g). After stirring for 5 minutes, the suspension was filtered and the filter cake was washed with heptane (10 g). The filtrate was transferred to a 125mL autoclave, washed with heptane (10 g), and Pd/C (150 mg,5% Pd,0.071mmol,0.6 mol%) was added. The reactor was inertized with argon, stirred at 500rpm, heated to 80℃and finally pressurized with hydrogen to 2 bar for 2 hours. The reaction was cooled to room temperature, the suspension was filtered through a syringe filter (0.45 μm) and the filter cake was washed with heptane (21.7 g). The filtrate was concentrated in vacuo to give (all-rac) -5-ethyl-9, 13-dimethyltetradecan-2-one as a colorless oil (3.00 g, 96.4% by qNMR, 10.8mmol, 95% yield).
Characterization of the Compounds of formula (IV)
GC-MS:98.4 area%;
m/z(％)268(1,M + ),253[2,(M-CH 3 ) + ],239[1,(M-C 2 H 5 ) + ],210(14),155(4),141(5),124(15),113(10),95(11),85(20),71(100),57(36),43(80),29(7)。
1 H NMR(300MHz,CHLOROFORM-d)δ0.81-0.90(m,12H),0.99-1.44(m,16H),1.45-1.60(m,3H),2.15(s,3H),2.34-2.46(m,2H)ppm。
13 C NMR(75MHz,CHLOROFORM-d)δ10.73,10.77,19.69,19.71,22.61,22.71,24.0,24.8,25.61,25.68,27.06,27.11,28.0,29.8,32.8,33.3,37.3,37.5,38.5,39.4,41.26,41.29,209.6ppm。
example 6: a compound of formula (II-a): (all-rac) -6-ethyl-3,10,14-trimethylpentadec-1-ene- 3-alcohols
The reaction steps are as follows: c3 (s)
An oven-dried 25mL three-necked round bottom flask was charged with vinyl magnesium chloride (2.1 mL of a 1.6M solution in THF, 3.35mmol,1.5 eq.). A solution of 5-ethyl-9, 13-dimethyltetradecan-2-one (example 5) (0.65 g,2.24mmol, 92.3% as determined by qNMR) in anhydrous THF (2.2 mL) was added dropwise over 30 min at 23 ℃. The reaction was stirred for a further 2h at 23℃and then was treated with saturated NH 4 Cl solution (1 mL) was quenched. Heptane (10 mL) and brine (10 mL) were added. The aqueous phase was extracted with heptane (2X 10 mL). The combined organic phases were washed with brine (2X 10 mL), and with MgSO 4 Dried, filtered and concentrated in vacuo to give (all-rac) -6-ethyl-3,10,14-trimethylpentadec-1-en-3-ol as a colorless oil (0.70 g,2.0mmol, 84.7% purity by qNMR, 89% yield).
Characterization of the Compounds of formula (II-A)
GC-MS:97.4 area%;
m/z(％)296(0.1,M + ),278[1,(M-H 2 O) + ],236(2),207(2),193(2),151(3),137(3),123(9),109(5),95(5),81(6),71(100),57(13),43(23),29(2)。
1 H NMR(300MHz,CHLOROFORM-d)δ0.79-0.90(m,12H),1.06-1.44(m,22H),1.46-1.65(m,3H),5.05(dd J＝10.7,1.3Hz,1H),5.21(dd,J＝17.3,1.3Hz,1H),5.92(dd,J＝17.3,10.7Hz,1H)ppm。
13 C NMR(75MHz,CHLOROFORM-d)δ10.82,10.85,10.88,14.1,19.7,22.61,22.69,22.71,24.10,24.12,24.8,25.78,25.84,26.87,26.93,27.64,27.67,28.0,29.0,31.9,32.7,33.4,37.3,37.5,39.1,39.28,39.30,39.37,73.4,111.5,145.3ppm。
example 7: a compound of formula (I-a): (all-rac) -2- (3-ethyl-7, 11-dimethyldeca)Dialkyl group) -2, the amino group of which is, synthesis of 5,7, 8-tetramethyl chroman-6-ol
The reaction steps are as follows: b2 (s)
Into a 5mL round bottom flask equipped with a magnetic stirrer, a septum and an argon balloon was charged 2,3, 5-trimethylhydroquinone (0.21 g,1.34mmol,98%,1.0 eq.) ZnCl 2 (0.16 g,1.13mmol,98%,0.84 eq.) and suspended in ethyl acetate (1 mL) and concentrated HCl (22 mg,0.22mmol,0.17 eq.). The reaction was heated to 35 ℃ (oil bath). Then 6-ethyl-3,10,14-trimethylpentadec-1-en-3-ol (example 6) (0.47 g,1.34mmol, 84.7% by qNMR, 1.0 eq.) was added over 30 minutes via syringe. Subsequently, the reaction was stirred at 35 ℃ for 2 hours. The mixture was then eluted with heptane (5 mL) and water (2.5 mL). The aqueous phase was extracted with heptane (5 mL). The combined organic phases were washed with water (2X 2.5 mL), 10% NaHCO 3 Aqueous (2.5 mL) and brine (2.5 mL). The organic phase was dried over MgSO 4 The resulting mixture was dried over, filtered, and concentrated in vacuo to give (all-rac) -2- (3-ethyl-7, 11-dimethyldodecyl) -2,5,7, 8-tetramethyl chroman-6-ol as a brown oil (0.51 g,1.05mmol, 88.8% by qNMR, 78% yield).
Characterization of the Compounds of formula (I-A)
GC-MS:99.5 area%;
m/z(％)430(89,M + ),205(13),165(100),121(6),91(2),71(3),57(6),43(14)。
1 h NMR (300 mhz, chromaform-d) delta 0.84 (t, j=7.4 hz, 3H), overlapping peaks 0.85 (d, j=6.4 hz, 3H), 0.88 (d, j=6.8 hz, 6H), 1.03-1.42 (m, 18H), overlapping peaks 1.23 (s, 3H), 1.44-1.63 (m, 3H), 1.69-1.93 (m, 2H), 2.12 (s, 6H), 2.17 (s, 3H), 2.61 (t, j=6.9 hz, 2H), 4.17 (s, 1H, oh) ppm.
13 C NMR(75MHz,CHLOROFORM-d)δ10.81,10.86,10.89,10.93,11.3,11.8,12.2,19.7,20.8,22.6,22.7,23.7,24.07,24.16,24.8,25.78,25.85,25.90,25.97,26.45,26.51,28.0,31.37,31.39,32.78,33.43,33.54,36.50,36.53,36.57,37.4,37.5,39.2,39.4,74.6,117.3,118.4,121.0,122.6,144.5,145.6ppm。
Implementation of the embodimentsExample 8: examples of compounds of formula (I-B): (all-rac) -2- (3-ethyl-7, 11-dimethyldodecanol) Synthesis of alkyl) -2,5,7, 8-tetramethyl chroman-6-yl acetate
The reaction steps are as follows: a2 (s)
2- (3-ethyl-7, 11-dimethyldodecyl) -2,5,7, 8-tetramethyl-chroman-6-ol (example 7) (0.41 g,0.85mmol, 88.8% by qNMR, 1.0 eq.) was added to a 5mL round bottom flask equipped with a magnetic stirrer, condenser, and argon adapter and dissolved in acetic anhydride (0.23 mL,0.24g,99%,2.8 eq.) and pyridine (13.7 ul,13.4mg,0.17mmol,99.8%,0.2 eq.) and heated to 90 ℃ (oil bath) for 1.5 hours. The reaction was cooled to room temperature and then concentrated in vacuo to give the crude product (476 mg).
Purification by flash chromatography (silica gel, heptane/ethyl acetate gradient, 100:0 to 90:10 v/v) afforded (all-rac) -2- (3-ethyl-7, 11-dimethyldodecyl) -2,5,7, 8-tetramethyl chroman-6-ylacetate as a pale yellow oil (399mg, 0.79mmol, 94.9% by qNMR, 93% yield).
Characterization of Compounds of formula (I-B)
GC-MS:99.7 area%;
m/z(％)472(11M + ),430[100,(M-Ac) + ],247(4),207(20),165(56),121(3),91(2),71(3),57(7),43(16)。
1 h NMR (300 mhz, chromaform-d) delta 0.85 (t, j=7.2 hz, 3H), overlapping peaks 0.86 (d, j=6.40 hz, 3H), 0.88 (d, j=6.6 hz, 6H), 1.06-1.42 (m, 18H), overlapping peaks 1.24 (s, 3H), 1.45-1.64 (m, 3H), 1.68-1.90 (m, 2H), 1.99 (s, 3H), 2.04 (s, 3H), 2.11 (s, 3H), 2.34 (s, 3H), 2.60 (t, j=6.8 hz, 2H) ppm.
13 C NMR(75MHz,CHLOROFORM-d)δ10.82,10.84,10.86,10.91,11.8,12.1,12.9,19.7,20.55,20.60,22.62,22.71,24.09,24.15,24.8,25.76,25.84,25.87,25.94,26.41,26.48,28.0,32.8,33.42,33.51,37.3,37.5,39.1,39.4,75.2,117.3,123.0,124.9,126.6,140.5,149.4,169.7ppm。
Olfactory properties
The odor of each substance was tested by different test persons by sniffing the odor strips with the individual substances deposited thereon with a straw. Table 1 summarizes the olfactory impressions summarized in table 1.
Examples Compounds of formula (I) Annotating Annotating
Example 1 (IX) - Cellar, mildewed smell
Example 2 (VIII) Fruit flavor, pear Fruit flavor, pear
Example 3 (VII) Moist wood Fruit flavor, pear
Example 4 (VI) Fragrance composition -
Example 5 (IV) Chocolate, bean -
TABLE 1 olfactory impression of the compounds
Oxidation resistance
a) Determination of oxidative stability by determining induction period
Using Rannimat TM Oxidative stability was assessed (Metrohm AG of Zofingen, switzerland). Rannimat TM The oxidation of the liquid product is intended to be monitored. In principle, heated clean air was passed through the sample and the volatile oxidation products were transferred to a deionized water flask. Monitoring the conductivity of water through electrodes, volatile oxidation products (e.g., acetic acid or other charged molecules) can cause the conductivity of water to increase over time. These oxidation processes begin slowly but exponentially accelerate after an induction time that indicates the oxidative stability of the compound or sample (DGF standard method C-VI 6f (06)). Thus, the longer the induction time measured, the higher the antioxidant activity.
About 1g of 2- (3-ethyl-7, 11-dimethyldodecyl) -2,5,7, 8-tetramethyl-chroman-6-ol (example 7) or alpha-tocopherol (reference 1) was charged into Ransimat TM In a flask and placed inside the apparatus. Clean air at 80 ℃ was blown through the sample into a plastic flask containing deionized water (MilliQ water) and the conductivity of the water was measured continuously. The data was visualized by plotting time on the x-axis and conductivity on the y-axis. The slope of the resulting plot slowly increases until the induction time is reached. The rapid increase in slope of the curve indicates an exponential increase in oxidation. The induction time was determined manually from the intersection of the tangents and is summarized in table 2.
Examples Induction time [ hr ]]
Example 7 42
Reference 1 31
TABLE 2 passage through Rannimat at 80℃ TM Testing the oxidation stability obtained
Table 2 shows that the induction time is 35% longer than the antioxidant activity of alpha-tocopherol, which is well known for its antioxidant activity.
b) Determination of antioxidant Activity by reaction with 2,2' -biphenyl-1-picrylhydrazyl (DPPH)
The determination of antioxidant activity was further evaluated by a validated colorimetric method (Planck, szpylka, sapirstein, woolard, zapf, lee, chen, liu, tsao, dusterlov, baugh, determination of the antioxidant activity by reaction with, 2' -Diphenyl-1-Picrylhydrazyl (DPPH): collaborative Study first Action 2012.04,J AOAC,95,2012:1562-9).
In principle, the antioxidant is dissolved in water, methanol, and an aliquot of the solution is reacted with a pink stable free radical DPPH. This reaction resulted in the formation of a colourless antioxidant-DPPH adduct and the colour reduction can be quantified spectrophotometrically at 517 nm. The assay was calibrated with the water-soluble antioxidant Trolox.
About 25mg of 2- (3-ethyl-7, 11-dimethyldodecyl) -2,5,7, 8-tetramethyl chroman-6-ol (example 7) or alpha-tocopherol (reference 1) was dissolved in 50mL of methanol/water (40:10, v/v). 0.4mL of these solutions were added to DPPH reagent solution (about 40 mg/L), mixed and kept in the dark for 30 minutes. The aqueous solution was measured spectrophotometrically at 517nm relative to a blank distillation. In parallel, calibration curves using Trolox (=6-hydroxy-2, 5,7, 8-tetramethyl chromane-2-carboxylic acid) were prepared at 100, 200, 300, and 400 μg/mL according to the methods described above.
The antioxidant activity of both compounds was calculated as Trolox equivalents and is reported in table 3.
Examples Trolox equivalent
Example 7 1.17
Reference 1 1.15
TABLE 3 DPPH test Performance against Trolox
Table 3 shows that example 7 and reference 1 have higher antioxidant activity than Trolox, a well-recognized antioxidant.
In addition, table 3 shows that example 7 shows higher antioxidant activity than α -tocopherol (reference 1).
c) Oxidation-reduction potential
Cyclic voltammetry experiments were performed with PGSTAT128N (Metrohm Autolab). The electrochemical cell consists of a three-electrode system: vitreous carbon working electrode (BASI MF-2012), platinum wire counter electrode and LiCIO with 0.1M 4 An Ag/Ag+ reference electrode of ethanol-acetonitrile (1:1) solution. The working electrode was cleaned with a polishing cloth (Buehler) impregnated with 0.05mm alumina slurry and sonicated. Between runs, the electrodes were rinsed with solvent and dried with no-powder paper.
By dissolving example 7 in the previously prepared 0.1M LiCIO 4 Ethanol-ethanolA10 mM stock solution of 2- (3-ethyl-7, 11-dimethyldodecyl) -2,5,7, 8-tetramethyl chroman-6-ol was prepared in nitrile (1:1) buffer (example 7).
The stock solution was then incorporated into a 0.1M LiCIO 4 Ethanol-acetonitrile (1:1) buffer solution to obtain the desired analyte concentration. Cyclic voltammetry experiments were performed by the following steps: the potential (scan rate: 0.05V/s, potential step: 0.001V) is scanned, the anodic wave is first obtained (from 0V to 0.7V), and then the potential is cycled from 0.7V back to 0V for acquisition of the cathodic wave.
Fig. 3 shows the applied voltage (E) in volts and the measured current (I) in microamps of example 7 in x-axis at a concentration of 200 μm (dashed line) or 400 μm (solid line), respectively.
The redox potential of example 7 was taken from the cathode wave of the voltammetry, i.e. the maximum peak in fig. 3, and is recorded in table 4.
Concentration of Oxidation-reduction potential
200μM 0.38V
400μM 0.43V
Table 4. Redox potential of example 7.
The redox potential values measured electrochemically clearly demonstrate that 2- (3-ethyl-7, 11-dimethyldodecyl) -2,5,7, 8-tetramethyl chroman-6-ol (example 7) has excellent antioxidant properties.

Claims (19)

1. A compound of formula (I)
Figure FDA0004164982820000011
Wherein R is 1 、R 3 And R is 4 Independently of one another, hydrogen or methyl;
R 2 represents hydrogen or R 2 '，R 2 ' is a phenolic protecting group;
wherein each x marks a chiral/stereogenic center, and # marks a chiral/stereogenic center; and is also provided with
R 2 ' is selected from the group consisting of:
Figure FDA0004164982820000012
wherein R is 10 And R is 11 Independently of each other, represent C 1-15 -alkyl or fluorinated C 1-15 -alkyl or C 1-15 -cycloalkyl or C 7-15 -an aralkyl group;
R 12 represent C 1-15 Alkylene or C 6-15 -an alkylene group;
and wherein either
R 13 Represent C 1-15 -alkyl or alkylene oxyalkyl or polyoxyalkylene;
R 14 represents hydrogen or C 1-15 -an alkyl group;
either or
R 13 And R is 14 Together represent C forming a 5-to 7-membered ring 3-7 -an alkylene group;
and wherein Y is 1 、Y 2 And Y 3 Independently of one another, hydrogen or a group of the formula
Figure FDA0004164982820000021
And wherein the single dot-dashed line represents a bond through which the substituent is bound to the remainder of the molecule.
2. The compound of claim 1, wherein the compound of formula (I) is a compound of formula (I-a)
Figure FDA0004164982820000022
Each of which marks chiral/stereogenic centers, and # marks chiral/stereogenic centers.
3. A compound of formula (IV)
Figure FDA0004164982820000023
Each of which marks a chiral/stereogenic center.
4. Process for preparing compounds of formula (IV)
Figure FDA0004164982820000024
Comprises the following steps
d) Hydrogenating the compound of formula (VI) to obtain the compound of formula (IV)
Figure FDA0004164982820000031
Wherein the dashed line represents a carbon-carbon double bond at one of the two indicated positions.
5. Compounds of formula (VI)
Figure FDA0004164982820000032
Wherein the dashed line represents a carbon-carbon double bond at one of the two indicated positions; and is also provided with
Each of which marks a chiral/stereogenic center.
6. A compound of formula (VII)
Figure FDA0004164982820000033
Wherein the dashed line represents a carbon-carbon double bond at one of the two indicated positions; and is also provided with
Each of which marks a chiral/stereogenic center.
7. Process for preparing compounds of formula (II-A)
Figure FDA0004164982820000034
Comprises the following steps
b) Providing a compound of formula (IV);
Figure FDA0004164982820000035
The next step is
Either or
c1 Ethynylation of a compound of formula (IV) with acetylene in the presence of a basic substance to give a compound of formula (V)
Figure FDA0004164982820000041
c2 Hydrogenation of the compound of formula (V) with molecular hydrogen in the presence of a Lindlar catalyst to give the compound of formula (II-A);
either or
c3 Vinyl-forming a compound of formula (IV) by adding a vinyl grignard reagent to obtain a compound of formula (II-a);
each of which marks a chiral/stereogenic center.
8. The process according to claim 7, wherein the compound of formula (IV) is prepared according to the process of claim 7.
9. A compound of formula (V)
Figure FDA0004164982820000042
Each of which marks a chiral/stereogenic center.
10. Compounds of formula (II-A)
Figure FDA0004164982820000043
Each of which marks a chiral/stereogenic center.
11. A process for preparing a compound of formula (II-B) by isomerisation of a compound of formula (II-A),
Figure FDA0004164982820000044
Figure FDA0004164982820000051
wherein each is labeled chiral/stereogenic center;
and wherein the wavy line indicates a carbon-carbon bond which is in the Z-configuration or E-configuration when connected to a carbon-carbon double bond.
12. Compounds of formula (II-B)
Figure FDA0004164982820000052
Wherein each is labeled chiral/stereogenic center;
and wherein the wavy line indicates a carbon-carbon bond which is in the Z-configuration or E-configuration when connected to a carbon-carbon double bond.
13. A process for preparing a compound of formula (I-a), comprising the steps of:
b1 Providing a compound of formula (II-A) or (II-B);
Figure FDA0004164982820000053
b2 Condensing a compound of formula (II-A) or (II-B) with a compound of formula (III) to give a compound of formula (I-A)
Figure FDA0004164982820000054
Figure FDA0004164982820000061
Wherein R is 1 、R 3 And R is 4 Independently of one another, hydrogen or methyl;
wherein each x marks a chiral/stereogenic center, and # marks a chiral/stereogenic center;
and wherein the wavy line indicates a carbon-carbon bond which is in the Z-configuration or E-configuration when connected to a carbon-carbon double bond.
14. The method of claim 13, wherein the step of determining the position of the probe is performed,
a compound of formula (II-a) prepared according to the process of claim 7 or 8;
or alternatively
The compound of formula (II-B) is prepared according to the process of claim 11.
15. A process for preparing a compound of formula (I-B), comprising the steps of:
a1 Providing a compound of formula (I-A)
Figure FDA0004164982820000062
a2 Reacting a compound of formula (I-A) with a protecting agent to give a compound of formula (I-B)
Figure FDA0004164982820000063
Wherein R is 1 、R 3 And R is 4 Independently of one another, hydrogen or methyl; and is also provided with
R 2 ' represents a phenolic protecting group;
wherein each x marks a chiral/stereogenic center, and # marks a chiral/stereogenic center; and is also provided with
R 2 ' is selected from the group consisting of:
Figure FDA0004164982820000071
wherein R is 10 And R is 11 Independently of each other, represent C 1-15 -alkyl or fluorinated C 1-15 -alkyl or C 1-15 -cycloalkyl or C 7-15 -an aralkyl group;
R 12 represent C 1-15 Alkylene or C 6-15 -an alkylene group;
and wherein either
R 13 Represent C 1-15 -alkyl or alkylene oxyalkyl or polyoxyalkylene;
R 14 represents hydrogen or C 1-15 -an alkyl group;
either or
R 13 And R is 14 Together represent C forming a 5-to 7-membered ring 3-7 -an alkylene group;
and wherein Y is 1 、Y 2 And Y 3 Independently of one another, hydrogen or a group of the formula
Figure FDA0004164982820000072
And wherein the single dot-dashed line represents a bond through which the substituent is bound to the remainder of the molecule.
16. A composition comprising a compound of formula (I) and a compound of formula (XI),
Figure FDA0004164982820000081
wherein R is 1 、R 3 And R is 4 Independently of one another, hydrogen or methyl;
R 2 represents hydrogen or R 2 '，R 2 ' is a phenolic protecting group;
wherein each x marks a chiral/stereogenic center, and # marks a chiral/stereogenic center; and is also provided with
R 2 ' is selected from the group consisting of:
Figure FDA0004164982820000082
wherein R is 10 And R is 11 Independently of each other, represent C 1-15 -alkyl or fluorinated C 1-15 -alkyl or C 1-15 -cycloalkyl or C 7-15 -an aralkyl group;
R 12 represent C 1-15 Alkylene or C 6-15 -an alkylene group;
and wherein either
R 13 Represent C 1-15 -alkyl or alkylene oxyalkyl or polyoxyalkylene;
R 14 represents hydrogen or C 1-15 -an alkyl group;
either or
R 13 And R is 14 Together represent C forming a 5-to 7-membered ring 3-7 -an alkylene group;
and wherein Y is 1 、Y 2 And Y 3 Independently of one another, hydrogen or a group of the formula
Figure FDA0004164982820000091
And wherein the single dot-dashed line represents a bond through which the substituent is bound to the remainder of the molecule.
17. Use of a compound of formula (I) according to any one of claims 1 to 2 as an antioxidant.
18. Use of compounds of formula (IV), (VI), and (VII) according to any of claims 3, 5, or 6 in the flavor and fragrance field.
19. Use of a compound of formula (IV), (VI), and (VII) according to any of claims 3, 5, or 6 in the field of perfumes.
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